tbuckley/cabot-search huggingface dataset:
Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia
Authors: Longlong Tu, Jonathan C. Bean, Yang He, Hailan Liu, Meng Yu, Hesong Liu, Nan Zhang, Na Yin, Junying Han, Nikolas A. Scarcelli, Kristine M. Conde, Mengjie Wang, Yongxiang Li, Bing Feng, Peiyu Gao, Zhao-Lin Cai, Makoto Fukuda, Mingshan Xue, Qingchun Tong, Yongjie Yang, Lan Liao, Jianming Xu, Chunmei Wang, Yanlin He, Yong Xu
Journal: Journal of Clinical Investigation (2023)

Although glucose is the basic fuel essential to maintain the viability and functions of all cells, some neurons, namely glucose-inhibited (GI) neurons, paradoxically increase their firing activities when glucose falls and are inhibited by high glucose. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here we showed that currents mediated by anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of non-Ano4 neurons in the VMH suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.
Letter to the Editor: Acute rejection after liver transplantation with machine perfusion versus static cold storage: A systematic review and meta-analysis
Authors: Yu Gu, Tian Yu, Yang Xiang
Journal: Hepatology (2023)

1Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, National Clinical Research Center for Obstetric & Gynecologic Diseases, Beijing, Chinese Academy of Medical Sciences, Beijing, China 2Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Ethical approval: None. Research registration unique identifying number (UIN): None. Guarantor: Haifeng Xu. Provenance and peer review: Commentary, internally reviewed. Declaration of competing interest: None to declare. Correspondence Yang Xiang, Peking Union Medical College Hospital. Email: [email protected]
Bio-impedance spectroscopy added to a fluid management protocol does not improve preservation of residual kidney function in incident hemodialysis patients in a randomized controlled trial
Authors: Simon J. Davies, David Coyle, Elizabeth J. Lindley, David Keane, John Belcher, Fergus J. Caskey, Indranil Dasgupta, Andrew Davenport, Ken Farrington, Sandip Mitra, Paula Ormandy, Martin Wilkie, Jamie MacDonald, Mandana Zanganeh, Lazaros Andronis, Ivonne Solis-Trapala, Julius Sim
Journal: Kidney International (2023)

Avoiding excessive dialysis-associated volume depletion may help preserve residual kidney function (RKF). To establish whether knowledge of the estimated normally hydrated weight from bioimpedance measurements (BI-NHW) when setting the post-hemodialysis target weight (TW) might mitigate rate of loss of RKF, we undertook an open label, randomized controlled trial in incident patients receiving HD, with clinicians and patients blinded to bioimpedance readings in controls. A total of 439 patients with over 500 ml urine/day or residual GFR exceeding 3 ml/min/1.73m2 were recruited from 34 United Kingdom centers and randomized 1:1, stratified by center. Fluid assessments were made for up to 24 months using a standardized proforma in both groups, supplemented by availability of BI-NHW in the intervention group. Primary outcome was time to anuria, analyzed using competing-risk survival models adjusted for baseline characteristics, by intention to treat. Secondary outcomes included rate of RKF decline (mean urea and creatinine clearance), blood pressure and patient-reported outcomes. There were no group differences in cause-specific hazard rates of anuria (0.751; 95% confidence interval (0.459, 1.229)) or sub-distribution hazard rates (0.742 (0.453, 1.215)). RKF decline was markedly slower than anticipated, pooled linear rates in year 1: -0.178 (-0.196, -0.159)), year 2: -0.061 (-0.086, -0.036)) ml/min/1.73m2/month. Blood pressure and patient-reported outcomes did not differ by group. The mean difference agreement between TW and BI-NHW was similar for both groups, Bioimpedance: -0.04 kg; Control: -0.25 kg. Thus, use of a standardized clinical protocol for fluid assessment when setting TW is associated with excellent preservation of RKF. Hence, bioimpedance measurements are not necessary to achieve this.
Recent advances in the development of Rho kinase inhibitors (2015–2021)
Authors: Xiangrong Xu, Lei Yao
Journal: Medicinal Research Reviews (2023)

Rho-associated coiled-coil kinases (ROCKs) are key downstream effectors of small GTPases. ROCK plays a central role in diverse cellular events with accumulating evidence supporting the concept that ROCK is important in tumor development and progression. Numerous ROCK inhibitors have been investigated for their therapeutic potential in the treatment of cancers. In this article, we review recent research progress on ROCK inhibitors, especially those with potential for the treatment of cancers, reported in the literature from 2015 to 2021. Most ROCK inhibitors show potent in vitro and in vivo antitumor activities and have potential in the treatment of cancers.
The Internet of Animals: what it is, what it could be
Authors: Roland Kays, Martin Wikelski
Journal: Trends in Ecology & Evolution (2023)

One of the biggest trends in ecology over the past decade has been the creation of standardized databases. Recently, this has included live data, formal linkages between disparate databases, and automated analytics, a synergy that we recognize as the Internet of Animals (IoA). Early IoA systems relate animal locations to remote-sensing data to predict species distributions and detect disease outbreaks, and use live data to inform management of endangered species. However, meeting the future potential of the IoA concept will require solving challenges of taxonomy, data security, and data sharing. By linking data sets, integrating live data, and automating workflows, the IoA has the potential to enable discoveries and predictions relevant to human societies and the conservation of animals.
Effect of a Continuous Bedside Pressure Mapping System for Reducing Interface Pressures
Authors: Chester Ho, Wrechelle Ocampo, Danielle A. Southern, Darlene Sola, Barry Baylis, John M. Conly, David B. Hogan, Jaime Kaufman, Henry Thomas Stelfox, William A. Ghali
Journal: JAMA Network Open (2023)

Importance Continuous bedside pressure mapping (CBPM) technology can assist in detecting skin areas with excessive interface pressure and inform efficient patient repositioning to prevent the development of pressure injuries (PI). Objective To evaluate the efficacy of CBPM technology in reducing interface pressure and the incidence of PIs. Design, Setting, and Participants This parallel, 2-group randomized clinical trial was performed at a tertiary acute care center. The study started to enroll participants in December 2014 and was completed in May 2018. Participants included adults partially or completely dependent for bed mobility. Statistical analysis was performed from September 2018 to December 2022. Intervention Nursing staff using visual feedback from CBPM technology for 72 hours. Main Outcomes and Measures Absolute number of sensing points with pressure readings greater than 40 mm Hg, mean interface pressure across all sensing points under a patient’s body, proportion of participants who had pressure readings greater than 40 mm Hg, and pressure-related skin and soft tissue changes. Results There were 678 patients recruited. After attrition, 260 allocated to the control group (151 [58.1%] male; mean [SD] age, 61.9 [18.5] years) and 247 in the intervention group (147 [59.5%] male; mean [SD] age, 63.6 [18.1] years) were included in analyses. The absolute number of sensing points with pressures greater than 40 mm Hg were 11 033 in the control group vs 9314 in the intervention group ( P = .16). The mean (SD) interface pressure was 6.80 (1.63) mm Hg in the control group vs 6.62 (1.51) mm Hg in the intervention group ( P = .18). The proportion of participants who had pressure readings greater than 40 mm Hg was 99.6% in both the control and intervention groups. Conclusions and Relevance In this randomized clinical trial to evaluate the efficacy of CBPM technology in the reduction of interface pressure and the incidence of PIs in a tertiary acute care center, no statistically significant benefit was seen for any of the primary outcomes. These results suggest that longer duration of monitoring and adequately powered studies where CBPM feedback is integrated into a multifaceted intervention to prevent PI are needed. Trial Registration ClinicalTrials.gov Identifier: NCT02325388
The Mifepristone Case and the Legitimacy of the FDA
Authors: Abbe R. Gluck
Journal: JAMA (2023)

This Viewpoint discusses a recent federal court decision that invaliated the Food and Drug Administration’s (FDA) approval of mifepristone, a drug used to end pregnancies and manage miscarriage when used with misoprostol, and how that decision challenges the legitimacy and independence of the FDA.
In Support of Addressing Sensory Differences to Improve Preventive Dental Care Among Autistic Children
Authors: Kate E. Wallis, Daniel Fichter, Alexander G. Fiks
Journal: JAMA Network Open (2023)

Leah I. Stein Duker, PhD, OTR/L; Dominique H. Como, PhD, OTR/L; Caitlin Jolette, OTD, OTR/L; Cheryl Vigen, PhD; Cynthia L. Gong, PhD, PharmD; Marian E. Williams, PhD; José C. Polido, DDS, MS; Lucía I. Floríndez-Cox, PhD; Sharon A. Cermak, EdD, OTR/L
Preclinical Characterization and Phase I Trial Results of INBRX-109, A Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma
Authors: Vivek Subbiah, Sant P. Chawla, Anthony P. Conley, Breelyn A. Wilky, Anthony Tolcher, Nehal J. Lakhani, David Berz, Vasily Andrianov, William Crago, Monica Holcomb, Abrahim Hussain, Carson Veldstra, James Kalabus, Brianne O’Neill, Lane Senne, Emily Rowell, Analeah B. Heidt, Katelyn M. Willis, Brendan P. Eckelman
Journal: Clinical Cancer Research (2023)

Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4 months after first-line chemotherapy. No standard targeted therapies are available. We present the preclinical characterization of INBRX-109, a third-generation death receptor 5 (DR5) agonist, and clinical findings from a phase I trial of INBRX-109 in unresectable/metastatic chondrosarcoma (NCT03715933).INBRX-109 was first characterized preclinically as a DR5 agonist, with binding specificity and hepatotoxicity evaluated in vitro and antitumor activity evaluated both in vitro and in vivo. INBRX-109 (3 mg/kg every 3 weeks) was then evaluated in a phase I study of solid tumors, which included a cohort with any subtype of chondrosarcoma and a cohort with IDH1/IDH2-mutant conventional chondrosarcoma. The primary endpoint was safety. Efficacy was an exploratory endpoint, with measures including objective response, disease control rate, and PFS.In preclinical studies, INBRX-109 led to antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase I study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of 87.1% [27/31; durable clinical benefit, 40.7% (11/27)], including two partial responses, and median PFS of 7.6 months. Most treatment-related adverse events, including liver-related events, were low grade (grade ≥3 events in chondrosarcoma cohorts, 5.7%).INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase II trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.
Assessing the Gun Violence Archive as an Epidemiologic Data Source for Community Firearm Violence in 4 US Cities
Authors: Ariana N. Gobaud, Christina A. Mehranbod, Elinore Kaufman, Jonathan Jay, Jessica H. Beard, Sara F. Jacoby, Charles C. Branas, Brady Bushover, Christopher N. Morrison
Journal: JAMA Network Open (2023)

Firearm injury is a major public health burden in the US, and yet there is no single, validated national data source to study community firearm violence, including firearm homicide and nonfatal shootings that result from interpersonal violence.
Decoding the Fundamental Drivers of Phylodynamic Inference
Authors: Leo A Featherstone, Sebastian Duchene, Timothy G Vaughan
Journal: Molecular Biology and Evolution (2023)

Despite its increasing role in the understanding of infectious disease transmission at the applied and theoretical levels, phylodynamics lacks a well-defined notion of ideal data and optimal sampling. We introduce a method to visualize and quantify the relative impact of pathogen genome sequence and sampling times-two fundamental sources of data for phylodynamics under birth-death-sampling models-to understand how each drives phylodynamic inference. Applying our method to simulated data and real-world SARS-CoV-2 and H1N1 Influenza data, we use this insight to elucidate fundamental trade-offs and guidelines for phylodynamic analyses to draw the most from sequence data. Phylodynamics promises to be a staple of future responses to infectious disease threats globally. Continuing research into the inherent requirements and trade-offs of phylodynamic data and inference will help ensure phylodynamic tools are wielded in ever more targeted and efficient ways.
Recent Improvements in Data From the Gun Violence Archive—Will They Lead to Change?
Authors: Christopher M. Worsham, Anupam B. Jena
Journal: JAMA Network Open (2023)

Ariana N. Gobaud, MPH; Christina A. Mehranbod, MPH; Elinore Kaufman, MD; Jonathan Jay, DrPH; Jessica H. Beard, MD; Sara F. Jacoby, PhD; Charles C. Branas, PhD; Brady Bushover, MPH; Christopher N. Morrison, PhD
Long-term Outcomes of Bevacizumab and Chemoradiation for Locoregionally Advanced Nasopharyngeal Carcinoma
Authors: Nancy Y. Lee, Jonathan Harris, John Kim, Adam Garden, James Mechalakos, David G. Pfister, Anthony T.C. Chan, Kenneth Hu, A Dimitrios Colevas, Steven Frank, George Shenouda, Voichita Bar-Ad, John N. Waldron, Paul M. Harari, Adam Raben, Pedro Torres-Saavedra, Quynh-Thu Le
Journal: JAMA Network Open (2023)

The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC).
Prediction of Shock-Refractory Ventricular Fibrillation During Resuscitation of Out-of-Hospital Cardiac Arrest
Authors: Jason Coult, Betty Y. Yang, Heemun Kwok, J. Nathan Kutz, Patrick M. Boyle, Jennifer Blackwood, Thomas D. Rea, Peter J. Kudenchuk
Journal: Circulation (2023)

Out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation (VF) is associated with relatively poor survival. The ability to predict refractory VF (requiring ≥3 shocks) in advance of repeated shock failure could enable preemptive targeted interventions aimed at improving outcome, such as earlier administration of antiarrhythmics, reconsideration of epinephrine use or dosage, changes in shock delivery strategy, or expedited invasive treatments. We conducted a cohort study of VF out-of-hospital cardiac arrest to develop an ECG-based algorithm to predict patients with refractory VF. Patients with available defibrillator recordings were randomized 80%/20% into training/test groups. A random forest classifier applied to 3-s ECG segments immediately before and 1 minute after the initial shock during cardiopulmonary resuscitation was used to predict the need for ≥3 shocks based on singular value decompositions of ECG wavelet transforms. Performance was quantified by area under the receiver operating characteristic curve. Of 1376 patients with VF out-of-hospital cardiac arrest, 311 (23%) were female, 864 (63%) experienced refractory VF, and 591 (43%) achieved functional neurological survival. Total shock count was associated with decreasing likelihood of functional neurological survival, with a relative risk of 0.95 (95% CI, 0.93-0.97) for each successive shock (P<0.001). In the 275 test patients, the area under the receiver operating characteristic curve for predicting refractory VF was 0.85 (95% CI, 0.79-0.89), with specificity of 91%, sensitivity of 63%, and a positive likelihood ratio of 6.7. A machine learning algorithm using ECGs surrounding the initial shock predicts patients likely to experience refractory VF, and could enable rescuers to preemptively target interventions to potentially improve resuscitation outcome.
Pancreatic Neoplasms Are Frighteningly Common: A Role for Immune Surveillance?
Authors: Megan T. Hoffman, Stephanie K. Dougan
Journal: Cancer Discovery (2023)

Summary: Carpenter and colleagues analyze organ donors to find that pancreatic intraepithelial neoplasia (PanIN), the precursor lesions of pancreatic ductal adenocarcinoma, are highly prevalent in the average healthy adult starting from a young age. Why these precursor lesions do not progress to cancer in most people is a mystery. See related article by Carpenter et al., p. 1324 (1).
Type 2 inflammation and biological therapies in asthma: Targeted medicine taking flight
Authors: Imran Howell, Aleksandra Howell, Ian D. Pavord
Journal: The Journal of Experimental Medicine (2023)

The field of asthma has undergone a dramatic change in recent years. Advances in our understanding of type 2 airway inflammation have driven the discovery of monoclonal antibodies targeting specific aspects of the immune pathway. In landmark trials, these drugs have shown efficacy in reducing asthma attacks and exposure to oral corticosteroids, important causes of morbidity in people with asthma. Our review explores the key features of type 2 inflammation in asthma and summarizes the clinical trial evidence of the novel monoclonal antibody treatments and future avenues for treatment.
Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru
Authors: Pedro G Suárez, Katherine Floyd, Jaime Portocarrero, Edith Alarcón, Elisabetta Rapiti, Gilbert Ramos, Cesar Bonilla, Ivan Sabogal, Isabel Aranda, Christopher Dye, Mario Raviglione, Marcos A Espinal
Journal: The Lancet (2002)
Bridging the Gap between Diseases of the Stomach and Lower Esophagus
Authors: Matthew D. Stachler
Journal: Cancer Discovery (2023)

In this issue of Cancer Discovery, Nowicki-Osuch and colleagues perform an extensive characterization and analysis of single-cell RNA-sequencing data of the tubal gastrointestinal system, including a spectrum of inflammatory conditions and intestinal metaplasia of the stomach and esophagus. They show that both gastric and esophageal intestinal metaplasia share similarities at the transcript and protein levels. Interestingly, they show that individual cells within areas of metaplasia can coexpress transcriptional programs of both gastric and intestinal epithelia. See related article by Nowicki-Osuch et al., 1346 (6).
Effect of phosphodiesterase‐5 inhibition on <scp>SystEmic</scp> Right <scp>VEntricular</scp> size and function. A multicentre, double‐blind, randomized, placebo‐controlled trial: <scp>SERVE</scp>
Authors: Matthias Greutmann, Daniel Tobler, Reto Engel, Dik Heg, Christian Mueller, André Frenk, Harald Gabriel, Tobias Rutz, Ronny R. Buechel, Matthias Willhelm, Lukas Trachsel, Michael Freese, Francisco Javier Ruperti‐Repilado, Emanuela Valsangiacomo Buechel, Dietrich Beitzke, Philip Haaf, Kerstin Wustmann, Fabienne Schwitz, Mathias Possner, Juerg Schwitter, Judith Bouchardy, Markus Schwerzmann
Journal: European Journal of Heart Failure (2023)

In adults with congenital heart disease and systemic right ventricles, progressive right ventricular systolic dysfunction is common and is associated with adverse outcomes. Our aim was to assess the impact of the phosphodiesterase-5-inhibitor tadalafil on right ventricular systolic function.This was a double-blind, randomized, placebo-controlled, multicentre superiority trial (NCT03049540) involving 100 adults with systemic right ventricles (33 women, mean age: 40.7 ± 10.7 years), comparing tadalafil 20 mg once daily versus placebo (1:1 ratio). The primary endpoint was the change in right ventricular end-systolic volume after 3 years of therapy. Secondary endpoints were changes in right ventricular ejection fraction, exercise capacity and N-terminal pro-B-type natriuretic peptide concentration. Primary endpoint assessment by intention to treat analysis at 3 years of follow-up was possible in 83 patients (42 patients in the tadalafil group and 41 patients in the placebo group). No significant changes over time in right ventricular end-systolic volumes were observed in the tadalafil and the placebo group, and no significant differences between treatment groups (3.4 ml, 95% confidence interval -4.3 to 11.0, p = 0.39). No significant changes over time were observed for the pre-specified secondary endpoints for the entire study population, without differences between the tadalafil and the placebo group.In this trial in adults with systemic right ventricles, right ventricular systolic function, exercise capacity and neuro-hormonal activation remained stable over a 3-year follow-up period. No significant treatment effect of tadalafil was observed. Further research is needed to find effective treatment for improvement of ventricular function in adults with systemic right ventricles.
A systems and computational biology perspective on advancing CAR therapy
Authors: Vardges Tserunyan, Stacey D. Finley
Journal: Seminars in Cancer Biology (2023)

In the recent decades, chimeric antigen receptor (CAR) therapy signaled a new revolutionary approach to cancer treatment. This method seeks to engineer immune cells expressing an artificially designed receptor, which would endue those cells with the ability to recognize and eliminate tumor cells. While some CAR therapies received FDA approval and others are subject to clinical trials, many aspects of their workings remain elusive. Techniques of systems and computational biology have been frequently employed to explain the operating principles of CAR therapy and suggest further design improvements. In this review, we sought to provide a comprehensive account of those efforts. Specifically, we discuss various computational models of CAR therapy ranging in scale from organismal to molecular. Then, we describe the molecular and functional properties of costimulatory domains frequently incorporated in CAR structure. Finally, we describe the signaling cascades by which those costimulatory domains elicit cellular response against the target. We hope that this comprehensive summary of computational and experimental studies will further motivate the use of systems approaches in advancing CAR therapy.